Humanin Explained

Humanin is a micropeptide encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2. Its structure contains a three-turn α-helix, and no symmetry.

In in vitro and animal models, it appears to have cytoprotective effects.[1] [2] [3] [4]

Gene

Humanin is encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2.[5] Multiple paralogs are found in the nuclear genome (due to nuclear mitochondrial DNA segments) and are named MTRNR2L followed by a number. It is not entirely sure whether these paralogous isoforms are completely unexpressed.[6]

Protein

The expressed peptide[7] contains a three-turn α-helix, and has no symmetry.[7]

The length of the peptide depends on where it is produced. If it is produced inside the mitochondria it will be 21 amino acids long.[8] If it is produced outside the mitochondria, in the cytosol, it will be 24 amino acids long.[8] Both peptides have been shown to have biological activity.[8] [9]

Other species

Humanin is the most well-conserved of the mitochondria-derived peptides, found in such diverse species as humans, naked mole rats, and nematodes.[3] Overexpression of humanin in Caenorhabditis elegans has been shown to extend the lifespan of that nematode by increasing autophagy.[3]

The rat, Rattus norvegicus, has a gene, rattin ("Humanin-like protein"), that encodes a 38 amino acid peptide homologous to humanin.[10] The two genes produce cDNAs that show 88% sequence identity.[10] The peptides are 81% identical, with the carboxyl terminal sequence in rattin being 14 amino acids longer than in humanin.[10] Of the 24 amino acids in the rest of the rat sequence, 20 are identical to the amino acids in the human sequence.[10]

The mouse MT-RNR2 humanin ortholog is a pseudogene, so no humanin is produced from the mtDNA. However, the nuclear genome harbors (like in humans) many copies of mitochondrial genomes, and one copy of the humanin homolog, Gm20594, is actively expressed.[11]

Function

Humanin has several cytoprotective effects.[12]

Interactions

Extracellular interaction with a tripartite receptor composed of gp130, WSX1, and CNTFR, as well as interaction with the formyl peptide receptor 2 (formylpeptide-like-1 receptor) have been published.[13] [14]

Intracellular interaction with BAX, tBID, IGFBP3, and TRIM11 may also be required for the effects of humanin.[15] [16]

Discovery

Humanin was the first mitochondria-derived peptide to be discovered. Humanin was independently found by three different labs looking at different parameters. The first to publish, in 2001, was the Nishimoto lab, which found humanin while looking for possible proteins that could protect cells from amyloid beta, a major component of Alzheimer's disease. The Reed lab found humanin when screening for proteins that could interact with Bcl-2-associated X protein (Bax), a major protein involved in apoptosis. The Pinchas Cohen lab independently discovered humanin when screening for proteins that interact with IGFBP3.[17]

Research

Experiments using cultured cells have demonstrated that humanin has both neuroprotective as well as cytoprotective effects and experiments in rodents have found that it has protective effects in Alzheimer's disease models, Huntington's disease models and stroke models.[18]

Humanin is proposed to have myriad neuroprotective and cytoprotective effects. Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in Alzheimer's disease models.[19] [20] In addition to Alzheimer's disease, humanin has other neuroprotective effects against models of Huntington's disease, prion disease, and stroke.[21] [22] [23]

Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack.[24] [25] [26] [27] Humanin activates chaperone-mediated autophagy in a dose-dependent manner. Humanin decreases production of inflammatory cytokines, which is part of its anti-apoptotic effect. Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with type 1 diabetes,[28] and increases insulin sensitivity, which may help with type 2 diabetes.[29] In rats, the humanin analog appears to normalize glucose levels and reduce diabetes symptoms.[30]

Rattin shows the same ability as humanin to defend neurons from the toxicity of beta-amyloid, the cause of degeneration in Alzheimer's disease.[10]

Small humanin-like peptides are a group of peptides found in the mitochondrial 16S rRNA, and also possess retrograde signaling functions.

Notes and References

  1. Cai H, Liu Y, Men H, Zheng Y . Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases . . 12 . 683151 . 2021 . 10.3389/fendo.2021.683151 . 8222669 . 34177809 . free .
  2. Conte M, Martucci M, Franceschi C, Salvioli S . Mitochondria, immunosenescence and inflammaging: a role for mitokines? . Seminars in Immunopathology . 42 . 5 . 607–617 . 2020 . 10.1007/s00281-020-00813-0 . 7666292 . 32757036.
  3. Miller B, Kim S, Cohen P . Mitochondria-derived peptides in aging and healthspan . . 132 . 9 . e158449 . 2022 . 10.1172/JCI158449 . 9057581 . 35499074.
  4. Burtscher J, Soltany A, Khamoui AV . Mitochondrial stress and mitokines in aging . . 22 . 2 . e13770 . 2023 . 10.1111/acel.13770 . 9924952 . 36642986.
  5. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I . A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta . Proceedings of the National Academy of Sciences of the United States of America . 98 . 11 . 6336–41 . May 2001 . 11371646 . 33469 . 10.1073/pnas.101133498 . 2001PNAS...98.6336H . free .
  6. Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, Dembinska-Kiec A . Evidence for potential functionality of nuclearly-encoded humanin isoforms . Genomics . 94 . 4 . 247–56 . October 2009 . 19477263 . 10.1016/j.ygeno.2009.05.006 . free .
  7. Benaki D, Zikos C, Evangelou A, Livaniou E, Vlassi M, Mikros E, Pelecanou M . Solution structure of humanin, a peptide against Alzheimer's disease-related neurotoxicity . Biochemical and Biophysical Research Communications . 329 . 1 . 152–60 . April 2005 . 15721287 . 10.1016/j.bbrc.2005.01.100 . 2014-07-07 . 2015-02-08 . https://web.archive.org/web/20150208221157/http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=1Y32 . dead .
  8. Yen K, Lee C, Mehta H, Cohen P . The emerging role of the mitochondrial-derived peptide humanin in stress resistance . Journal of Molecular Endocrinology . 50 . 1 . R11-9 . February 2013 . 23239898 . 3705736 . 10.1530/JME-12-0203 . 2013 . Feb 2013 . hassy@usc.edu .
  9. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC . Humanin peptide suppresses apoptosis by interfering with Bax activation . Nature . 423 . 6938 . 456–61 . May 2003 . 12732850 . 10.1038/nature01627 . 2003Natur.423..456G . 4423176 .
  10. Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F . A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity . FASEB Journal . 16 . 10 . 1331–3 . August 2002 . 12154011 . 10.1096/fj.02-0018fje . free . 31415552 . 2002 . August 2002 . andrea.caricasole@uniroma1.it .
  11. Kim . J . Choi . JW . Namkung . J . Expression Profile of Mouse Gm20594, Nuclear-Encoded Humanin-Like Gene. . Journal of Lifestyle Medicine . 31 January 2021 . 11 . 1 . 13–22 . 10.15280/jlm.2021.11.1.13 . 33763338. 7957044 .
  12. Kim SJ, Xiao J, Wan J, Cohen P, Yen K . Mitochondrially derived peptides as novel regulators of metabolism . The Journal of Physiology . 595 . 21 . 6613–6621 . November 2017 . 28574175 . 5663826 . 10.1113/JP274472 .
  13. Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M . Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130 . Molecular Biology of the Cell . 20 . 12 . 2864–73 . June 2009 . 19386761 . 2695794 . 10.1091/mbc.E09-02-0168 .
  14. Ying G, Iribarren P, Zhou Y, Gong W, Zhang N, Yu ZX, Le Y, Cui Y, Wang JM . Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor . Journal of Immunology . 172 . 11 . 7078–85 . June 2004 . 15153530 . 10.4049/jimmunol.172.11.7078 . free .
  15. Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC . Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak . The Journal of Biological Chemistry . 280 . 16 . 15815–24 . April 2005 . 15661737 . 10.1074/jbc.M411902200 . free .
  16. Niikura T, Hashimoto Y, Tajima H, Ishizaka M, Yamagishi Y, Kawasumi M, Nawa M, Terashita K, Aiso S, Nishimoto I . A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults . The European Journal of Neuroscience . 17 . 6 . 1150–8 . March 2003 . 12670303 . 10.1046/j.1460-9568.2003.02553.x . 1345339 .
  17. Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P . Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis . Proceedings of the National Academy of Sciences of the United States of America . 100 . 22 . 13042–7 . October 2003 . 14561895 . 240741 . 10.1073/pnas.2135111100 . 2003PNAS..10013042I . free .
  18. Yen K, Lee C, Mehta H, Cohen P . The emerging role of the mitochondrial-derived peptide humanin in stress resistance . Journal of Molecular Endocrinology . 50 . 1 . R11-9 . February 2013 . 23239898 . 3705736 . 10.1530/JME-12-0203 .
  19. Tajima H, Kawasumi M, Chiba T, Yamada M, Yamashita K, Nawa M, Kita Y, Kouyama K, Aiso S, Matsuoka M, Niikura T, Nishimoto I . A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice . Journal of Neuroscience Research . 79 . 5 . 714–23 . March 2005 . 15678515 . 10.1002/jnr.20391 . 25194143 .
  20. Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I . Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults . The Journal of Neuroscience . 21 . 23 . 9235–45 . December 2001 . 11717357 . 6763898 . 10.1523/JNEUROSCI.21-23-09235.2001 .
  21. Kariya S, Hirano M, Nagai Y, Furiya Y, Fujikake N, Toda T, Ueno S . Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches . Journal of Molecular Neuroscience . 25 . 2 . 165–9 . 2005 . 15784964 . 10.1385/JMN:25:2:165 . 23766205 .
  22. Sponne I, Fifre A, Koziel V, Kriem B, Oster T, Pillot T . Humanin rescues cortical neurons from prion-peptide-induced apoptosis . Molecular and Cellular Neurosciences . 25 . 1 . 95–102 . January 2004 . 14962743 . 10.1016/j.mcn.2003.09.017 . 20276062 .
  23. Xu X, Chua CC, Gao J, Hamdy RC, Chua BH . Humanin is a novel neuroprotective agent against stroke . Stroke . 37 . 10 . 2613–9 . October 2006 . 16960089 . 10.1161/01.STR.0000242772.94277.1f . free .
  24. Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P, Lerman A . Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress . Cardiovascular Research . 88 . 2 . 360–6 . November 2010 . 20562421 . 2952532 . 10.1093/cvr/cvq191 .
  25. Oh YK, Bachar AR, Zacharias DG, Kim SG, Wan J, Cobb LJ, Lerman LO, Cohen P, Lerman A . Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice . Atherosclerosis . 219 . 1 . 65–73 . November 2011 . 21763658 . 3885346 . 10.1016/j.atherosclerosis.2011.06.038 .
  26. Zacharias DG, Kim SG, Massat AE, Bachar AR, Oh YK, Herrmann J, Rodriguez-Porcel M, Cohen P, Lerman LO, Lerman A . Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans . PLOS ONE . 7 . 2 . e31065 . 2012 . 22328926 . 3273477 . 10.1371/journal.pone.0031065 . Westermark . 2012PLoSO...731065Z . Per . free .
  27. Muzumdar RH, Huffman DM, Calvert JW, Jha S, Weinberg Y, Cui L, Nemkal A, Atzmon G, Klein L, Gundewar S, Ji SY, Lavu M, Predmore BL, Lefer DJ . Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice . Arteriosclerosis, Thrombosis, and Vascular Biology . 30 . 10 . 1940–8 . October 2010 . 20651283 . 2941397 . 10.1161/ATVBAHA.110.205997 .
  28. Hoang PT, Park P, Cobb LJ, Paharkova-Vatchkova V, Hakimi M, Cohen P, Lee KW . The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice . Metabolism . 59 . 3 . 343–9 . March 2010 . 19800083 . 2932671 . 10.1016/j.metabol.2009.08.001 .
  29. Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, Hwang D, Barzilai N, Cohen P . Humanin: a novel central regulator of peripheral insulin action . PLOS ONE . 4 . 7 . e6334 . July 2009 . 19623253 . 2709436 . 10.1371/journal.pone.0006334 . Vella . 2009PLoSO...4.6334M . Adrian . free .
  30. News: Hall. Stephen S.. New Clues to a Long Life. 30 August 2017. National Geographic. March 2012. 30 August 2017. https://web.archive.org/web/20170830235925/http://ngm.nationalgeographic.com/2013/05/longevity/hall-text. dead.

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